Intracellular ionized calcium serves as a second messenger for many mammalian cells, including some neurons, when its normally very low resting concentration is transiently elevated in response to hormonal, electrical, or mechanical stimuli. The plasma membrane of these cells contains an enzyme system which "pumps" the excess calcium out of the cells, thus restoring the resting condition in preparation for the next signal. This enzyme system consists of a membrane-bound calcium ATPase which is activated by soluble calmodulin in the cell when the calcium concentration increases. Since the same enzyme system exists in membranes of human erythrocytes, it is studied conveniently in blood samples which had been obtained for clinical purposes. Application of a sensitive and difficult technique, termed a "kinetic titration", yields three independent parameters which characterize this enzyme system. These are: the strength of binding of calmodulin to the enzyme, the membrane concentration of the enzyme that binds calmodulin, and the maximal velocity of the calmodulin-activated system. The results to date show clear differences between normals and bipolar patients with respect to some of these parameters. Parameter values also very with changes in mood and diagnostic category. The direction of all of these changes is such as to suggest that successful therapy during the depressive end of the cycle is associated with more effective calcium pumping. It is the specific aim of this study to explore these observations in more detail; the long term goal is directed toward an enlarged understanding of the role of intracellar calcium in mental illness.